This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PI3K has been implicated in cancer-associated deregulation through its function in cell survival signaling. Recently, it has been shown that PIK3CA mutations encoding the p110 catalytic subunit of PI3K appear to show gain of function and are frequent in colon cancer (~30%) as well as in other tumor types. PIK3CA mutation with its gain of function properties and the ability to identify patients bearing mutations raises the possibility of identifying novel targets for treatment in a specific subpopulation of patients. Of additional importance in this regard is that PIK3CA mutations appear to be a late occurring event in cancer progression and, therefore, may be associated with the metastatic process as the mutations are rare in adenomas. The potential relationship between PIK3CA mutations, cell survival signaling and metastasis is of note. We have shown that abrogation of autocrine TGFbeta enables increased PI3K/Akt/survivin activation in colon cancer cells under growth factor deprivation stress (GFDS), which shifts the balance towards survival. In addition, we have also identified a strong association between gain of function PIK3CA mutations, inappropriate constitutive PI3K/AKT signaling and survival under stress conditions and enhanced metastatic phenotype. Recently, in vivo and in vitro observations indicated that the metastatic potential of tumors is associated with an increased resistance to apoptosis. Therefore, the regulation of the metastatic process by inhibition of cell death has become an important field of study. An underlying theme for this project will be testing the hypothesis that the metastatic phenotype is dependent upon aberrant survival signaling conferred by gain of function PIK3CA mutations in concert with the inactivation of TGFbeta signaling.